This invention is directed to a method for synthesizing densely functionalized pyrrolidine intermediates. In particular, the invention is directed to a method for synthesizing highly substituted pyrrolidine intermediates both on and off solid supports. More particularly, the invention is directed to highly substituted pyrrolidine intermediates useful for the further in situ and resin-bound synthetic generation of chemical libraries.
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through molecular biology techniques or synthetic chemical techniques.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of xe2x80x9clead compoundsxe2x80x9d is typically altered to determine the effect of the alteration on activity. Alteration of the structure of the lead compound around a core xe2x80x9cscaffoldxe2x80x9d structure creates a plurality of compounds and permits evaluation of the effect of the structural alteration on activity.
The xe2x80x9clibraryxe2x80x9d of compounds thus created is derived from a single lead compound. Accordingly, a plurality of scaffolds and libraries can be created and screened by modifying the core of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e. those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be quickly identified from the initial lead compound.
The generation of chemical libraries both on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening techniques (Wu, Zengru et al, Beijing Daxue Xuebao, Ziran Kexueban 2000, 36(2), 275-285; Brummer, Oliver et al, Curr. Opin. Drug Discovery Dev., 2000, 3(4), 462-473; Roe, Diana C., Mol. Diversity Drug Des., 1999, 141-173; Barnes, Colin et al, Curr. Opin. Chem. Biol., 2000, 4(3), 346-350; Weber, Lutz, Curr. Opin. Chem. Biol., 2000, 4(3), 295-302).
In creating the libraries, the compounds are ideally synthesized on a solid support (resin-bound) or in solution phase (in situ or off-solid support). Relatively simple synthetic methods to produce a diverse collection of such derivatives in situ, though, are often not available.
The need for large numbers of compounds has led to the synthesis of compounds based on very simple templates. A number of peptidomimetic libraries based on amino acid modules have also been introduced (R. A. Owens et al, Biochem. Biophys. Res. Comm., 1991, 181, 402; P. F. Alewood et al, Tet. Lett., 1992, 33, 977; E. K. Kick and J. A. Ellman, J. Med. Chem., 1995, 38, 1427; G. T. Wang et al, J. Med. Chem., 1995, 38, 2995; J. Jiracek et al, J. Biol. Chem., 1995, 270 21701). Chiron""s peptoid approach led to a number of interesting starting points for analogs early in the library generation era (Zuckermann, Ronald N. et al, J. Am. Chem. Soc., 1992, 114(26), 10646-7). Amino acid based libraries have been used to address protein-protein interactions as well (Connolly, P. J. et al, Bioorg. Med. Chem. Lett., 2000, 10(17), 1995-1999; Connolly, P. J. et al, Tetrahedron Lett., 2000, 41(27), 5187-5191). Unfortunately, some of the more simple libraries have not yielded compounds that demonstrate significant biological activity.
More recently efforts have been made to develop chemistry that is amenable to library generation that produces molecules of considerable complexity for the purpose of creating more diverse chemical libraries. Recently electrocyclic reactions of amino acid derived dienes have been used to produce densely funtionalized octahydroquinolines and hexahydroisoindoles (Sun, Sengen et al, J. Org. Chem., 2000, 65(8), 2555-2559; Murray, William V. et al, J. Org. Chem., 1999, 64(16), 5930-5940; Sun, Sengen and Murray, William V., J. Org. Chem., 1999, 64(16), 5941-5945). Diels Alder reactions are useful synthetic methods either on or off solid support and allow for control of facial selectivity, endo versus exo selectivity and stereochemical selectivity at most of the ring positions.
Pyrrolidines are a class of molecules that have demonstrated diverse biological activity. PCT publication WO0056296 (published Sep. 28, 2000) describes substituted pyrrolidine compounds as dipeptidyl peptidase IV inhibitors for use in improving fertility. U.S. Pat. No. 5,935,980 (PCT publication WO9638139, published Dec. 5, 1996) describes substituted pyrrolidine compounds for use in treating alcoholism and associated conditions. U.S. Pat. No. 6,150,387 (PCT publication WO9728798, published Aug. 14, 1997) describes substituted pyrrolidine compounds for use in preventing or reducing drug dependence, pharmacomania or substance abuse and as useful CCK (cholecystokinin) and gastric receptor inhibitors for treating or preventing psychoses, anxiety disorders, Parkinson""s disease, tardive dyskinesia, irritable bowel syndrome, acute pancreatitis, ulcers, disorders of intestinal motility and certain CCK-sensitive tumors and as useful appetite regulators and analgesics. European patent application EP 24382 (published Mar. 4, 1981) describes substituted piperidine derivatives for use as local and topical anesthetics or for use as antiarrythmic agents.
Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate libraries of diverse pyrrolidine derivatives optionally attached to a solid support. An object of the present invention is to provide a facile in situ and resin-bound method for the generation of a multiplicity of densely functionalized pyrrolidine intermediates.
The present invention is directed to a method for generating densely functionalized pyrrolidine intermediates through the use of intramolecular Diels Alder reactions (via cycloaddition directed remote hydroxylation or amination) both on and off a solid support.
Accordingly, the present invention is directed to a method for generating densely functionalized pyrrolidine intermediates selected from the group consisting of Formula (I) and Formula (II): 
wherein
R1 is selected from the group consisting of a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain (wherein the amino acid side chain is optionally substituted with a suitable protecting group), hydrogen and xe2x80x94(C1-8)alkyl {wherein C1-8alkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of xe2x80x94CO2H (wherein CO2H is optionally substituted with a suitable protecting group), -phenyl-R6, -heteroaryl-R6 and hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group)}; alternatively, R1 and R2 may be joined to form a heterocyclyl ring;
R6 is one to two substituents selected from the group consisting of hydrogen, xe2x80x94(C1-8)alkyl, xe2x80x94Oxe2x80x94(C1-8)alkyl, halogen, hydroxy and nitro;
R2 is selected from the group consisting of hydrogen (wherein hydrogen is optionally replaced with a suitable protecting group), xe2x80x94(C1-8)alkyl, xe2x80x94(C1-8)alkyl-Phxe2x80x94R6, xe2x80x94C(O)xe2x80x94(C1-8)alkyl, xe2x80x94C(O)xe2x80x94Phxe2x80x94R6, xe2x80x94C(O)Oxe2x80x94(C1-8)alkyl, xe2x80x94C(O)Oxe2x80x94Phxe2x80x94R6, xe2x80x94C(O)Oxe2x80x94(C1-8)alkyl-Phxe2x80x94R6 and xe2x80x94SO2xe2x80x94Phxe2x80x94R6;
R3 is selected from the group consisting of xe2x80x94C(O)xe2x80x94N(R7R8), xe2x80x94CO2H (wherein CO2H is optionally substituted with a suitable protecting group), xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-8)alkyl and cyano;
R7 is selected from hydrogen, xe2x80x94(C1-8)alkyl, xe2x80x94(C1-8)alkyl-Phxe2x80x94R6, hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group) or a suitable protecting group;
R8 is selected from hydrogen, xe2x80x94(C1-8)alkyl, xe2x80x94(C1-8)alkyl-Phxe2x80x94R6 or a suitable protecting group;
R4 is selected from the group consisting of hydrogen, xe2x80x94(C1-8)alkyl and xe2x80x94(C1-8)alkyl-Phxe2x80x94R6;
R5 is selected from the group consisting of xe2x80x94(C1-8)alkyl and xe2x80x94Phxe2x80x94R6;
Y is optionally present and is selected from the group consisting of O and S;
X1 is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94N(H)xe2x80x94 (wherein NH is optionally substituted with a suitable protecting group), xe2x80x94N(xe2x80x94OH)xe2x80x94 (wherein hydroxy is optionally substituted with a suitable protecting group), xe2x80x94N(xe2x80x94Oxe2x80x94(C1-8)alkyl)xe2x80x94, xe2x80x94N(xe2x80x94C1-8alkyl-aryl-R6)xe2x80x94 and xe2x80x94N(xe2x80x94Oxe2x80x94(C1-8)alkyl-aryl-R6)xe2x80x94; and,
X2 is selected from the group consisting of xe2x80x94OH (wherein OH is optionally substituted with a suitable protecting group), xe2x80x94NH2 (wherein NH2 is optionally substituted with a suitable protecting group), xe2x80x94NH(xe2x80x94OH) (wherein NH and OH are optionally substituted with a suitable protecting group), xe2x80x94NH(xe2x80x94C1-8alkyl) (wherein NH is optionally substituted with a suitable protecting group) and xe2x80x94NH(xe2x80x94C1-8alkyl-aryl-R6) (wherein NH is optionally substituted with a suitable protecting group);
and pharmaceutically acceptable salts and diastereomers thereof;
wherein the method for generating an intermediate selected from the group consisting of Formula (I) and Formula (II)is either a resin-bound or an in-situ method comprising:
(a) preparing a compound of Formula (III): 
xe2x80x83(prepared as described in Sun, Sengen et al, J. Org. Chem., 2000, 65(8), 2555-2559; Murray, William V. et al, J. Org. Chem., 1999, 64(16), 5930-5940; Sun, Sengen and Murray, William V., J. Org. Chem., 1999, 64(16), 5941-5945) wherein R1 and R4 are as previously described; wherein R9 is selected from R2 (for an in-situ method) or (for a resin-bound method) is selected from xe2x80x94SO2xe2x80x94Phxe2x80x94CO2xe2x80x94 (resin) or xe2x80x94SO2xe2x80x94Phxe2x80x94C (O)xe2x80x94NHxe2x80x94 (resin); and, wherein R10 is selected from R3 (for an in-situ method) or (for a resin-bound method) is selected from xe2x80x94CO2xe2x80x94 (resin), xe2x80x94C(O)xe2x80x94NHxe2x80x94 (resin) or xe2x80x94C(N)-(resin); and,
(b) acylating the compound of Formula (III) to prepare a compound of Formula (IV): 
wherein Y, R1, R4, R5, R9 and R10 are as previously described; and, wherein X is selected from the group consisting of O, N(H) (wherein NH is optionally substituted with a suitable protecting group), N(xe2x80x94OH) (wherein hydroxy is optionally substituted with a suitable protecting group), N(xe2x80x94Oxe2x80x94(C1-8)alkyl), N(xe2x80x94C1-8alkyl-aryl-R6) and N(xe2x80x94Oxe2x80x94(C1-8)alkyl-aryl-R6);
(c) reacting the compound of Formula (IV) (with the proviso that the method is a resin-bound method) with the appropriate starting materials, using the appropriate reagents and conditions and cleaving the compound of Formula (IV) (with the proviso that the method is a resin-bound method) from the resin to prepare the intermediate selected from the group consisting of Formula (I) and Formula (II); or,
(d) refluxing the compound of Formula (IV) (with the proviso that the method is an in-situ method) using the appropriate reagents and conditions to prepare the intermediate selected from the group consisting of Formula (I) and Formula (II); wherein the intermediate is selected from a kinetic product (a trans isomer prepared at a reflux temperature of xe2x89xa680xc2x0 C.) or a thermodynamic product (a cis isomer prepared at a reflux temperature of  greater than 80xc2x0 C.);
alternatively, the method for preparing an intermediate of Formula (I) further comprises preparing a compound selected from Formula (IV) wherein X is NH(xe2x80x94OH); and, adding silica gel in the appropriate amount at the appropriate time and temperature to prepare the intermediate of Formula (I) by cycloaddition; and,
alternatively, the method for preparing an intermediate of Formula (II) further comprises hydrolyzing an intermediate of Formula (I) under the appropriate conditions to prepare the intermediate of Formula (II).
This invention is also directed to the use of the instant methods to prepare densely funtionalized pyrrolidine intermediates for use in synthesizing compound libraries.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R1 is selected from the group consisting of a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain (wherein the amino acid side chain is optionally substituted with a suitable protecting group), hydrogen and xe2x80x94(C1-4)alkyl {wherein C1-4alkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of xe2x80x94CO2H (wherein CO2H is optionally substituted with a suitable protecting group), -phenyl-R6, -heteroaryl-R6 and hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group)}; alternatively, R1 and R2 may be joined to form a heterocyclyl ring.
More preferably, R1 is selected from a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain optionally substituted with a suitable protecting group.
Preferably, when R1 is selected from a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain optionally substituted with a suitable protecting group, the amino acid side chain is selected from Ala, Val, Phe, Tyr, Ser, Thr, Asp, Glu and His.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R6 is one to two substituents selected from the group consisting of hydrogen, xe2x80x94(C1-4)alkyl, xe2x80x94Oxe2x80x94(C1-4)alkyl, halogen, hydroxy and nitro.
More preferably, R6 is one to two substituents selected from the group consisting of hydrogen, xe2x80x94Oxe2x80x94(C1-4)alkyl, halogen and nitro.
Most preferably, R6 is one to two substituents selected from the group consisting of hydrogen, methoxy, bromine and nitro.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R2 is selected from the group consisting of hydrogen (wherein hydrogen is optionally replaced with a suitable protecting group), xe2x80x94(C1-4)alkyl, xe2x80x94(C1-4)alkyl-Phxe2x80x94R6, xe2x80x94C(O)xe2x80x94(C1-4)alkyl, xe2x80x94C(O)xe2x80x94Phxe2x80x94R6, xe2x80x94C(O)Oxe2x80x94(C1-4)alkyl, xe2x80x94C(O)Oxe2x80x94Phxe2x80x94R6, xe2x80x94C(O)Oxe2x80x94(C1-4)alkyl-Phxe2x80x94R6 and xe2x80x94SO2xe2x80x94Phxe2x80x94R6.
More preferably, R2 is selected from the group consisting of xe2x80x94(C1-4)alkyl, xe2x80x94(C1-4)alkyl-Phxe2x80x94R6, xe2x80x94C(O)Oxe2x80x94(C1-4)alkyl, xe2x80x94C(O)Oxe2x80x94(C1-4)alkyl-Phxe2x80x94R6 and xe2x80x94SO2xe2x80x94Phxe2x80x94R6.
Most preferably, R2 is selected from xe2x80x94(C1-4)alkyl-Phxe2x80x94R6.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R3 is selected from the group consisting of xe2x80x94C(O)xe2x80x94N(R7R8), xe2x80x94CO2H (wherein CO2H is optionally substituted with a suitable protecting group), xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-4)alkyl and cyano.
More preferably, R3 is selected from the group consisting of xe2x80x94CO2H (wherein CO2H is optionally substituted with a suitable protecting group), xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-4)alkyl and cyano.
Most preferably, R3 is selected from xe2x80x94C(O)xe2x80x94Cxe2x80x94(C1-4)alkyl.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R7 is selected from hydrogen, xe2x80x94(C1-4)alkyl, xe2x80x94(C1-4)alkyl-Phxe2x80x94R6, hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group) or a suitable protecting group.
More preferably, R7 is selected from hydrogen, xe2x80x94(C1-4)alkyl or a suitable protecting group.
Most preferably, R7 is hydrogen.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R8 is selected from hydrogen, xe2x80x94(C1-4)alkyl, xe2x80x94(C1-4)alkyl-Phxe2x80x94R6 or a suitable protecting group.
More preferably, R8 is selected from hydrogen, xe2x80x94(C1-4)alkyl or a suitable protecting group.
Most preferably, R8 is hydrogen.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R4 is selected from the group consisting of hydrogen, xe2x80x94(C1-4)alkyl and xe2x80x94(C1-4)alkyl-Phxe2x80x94R6.
More preferably, R4 is selected from the group consisting of hydrogen and xe2x80x94(C1-4)alkyl.
Most preferably, R4 is hydrogen.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, R5 is selected from the group consisting of xe2x80x94(C1-4)alkyl and xe2x80x94Phxe2x80x94R6.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, Y is present and is selected from the group consisting of O and S.
More preferably, Y is present and is O.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, X1 is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94N(H)xe2x80x94, (wherein NH is optionally substituted with a suitable protecting group), xe2x80x94N(xe2x80x94OH)xe2x80x94 (wherein hydroxy is optionally substituted with a suitable protecting group), xe2x80x94N(xe2x80x94Oxe2x80x94(C1-4)alkyl)xe2x80x94, xe2x80x94N(xe2x80x94C1-4alkyl-aryl-R6)xe2x80x94 and xe2x80x94N(xe2x80x94Oxe2x80x94(C1-4)alkyl-aryl-R6)xe2x80x94.
More preferably, X1 is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94N(xe2x80x94OH)xe2x80x94 (wherein hydroxy is optionally substituted with a suitable protecting group).
Most preferably, X1 is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94N(xe2x80x94OH)xe2x80x94.
Embodiments of the present invention include intermediates selected from the group consisting of Formula (I) and Formula (II) wherein, preferably, X2 is selected from the group consisting of OH (wherein OH is optionally substituted with a suitable protecting group), xe2x80x94NH2 (wherein NH2 is optionally substituted with a suitable protecting group), xe2x80x94NH(xe2x80x94OH) (wherein NH and OH are optionally substituted with a suitable protecting group), xe2x80x94NH(xe2x80x94C1-4alkyl) (wherein NH is optionally substituted with a suitable protecting group) and xe2x80x94NH(xe2x80x94C1-4alkyl-aryl-R6) (wherein NH is optionally substituted with a suitable protecting group).
More preferably, X2 is selected from the group consisting of OH (wherein OH is optionally substituted with a suitable protecting group), xe2x80x94NH(xe2x80x94OH) (wherein NH and OH are optionally substituted with a suitable protecting group) and xe2x80x94NH(xe2x80x94C1-4alkyl-aryl-R6) (wherein NH is optionally substituted with a suitable protecting group).
Embodiments of the present invention include intermediates selected from Formula (I) wherein the intermediate is selected from Formula (Ia): 
wherein X1, R1, R2, R3 and R5 are dependently selected from the up consisting of:
and pharmaceutically acceptable salts and diastereomers thereof.
Embodiments of the present invention include intermediates selected from Formula (II) wherein an intermediate is selected from Formula (IIa): 
wherein X2 and R5 dependently selected from the group consisting of:
and pharmaceutically acceptable salts and diastereomers thereof.
Embodiments of the present invention include compounds selected from Formula (IV) wherein a compound is selected from Formula (IVa): 
wherein X, R1, R5, R9 and R10 are dependently selected from the group consisting of:
and pharmaceutically acceptable salts and enantiomers thereof.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1). Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The compounds according to this invention possess one or more chiral centers and thus may exist as enantiomers, diastereomers and enantiomer/diastereomers. Where the processes for the preparation of the present compounds give rise to a mixture of such isomers, the isomers may be separated by conventional techniques such as preparative chromatography. Alternatively, the isomers may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
Unless specified otherwise, the term xe2x80x9calkylxe2x80x9d refers to a saturated straight or branched chain consisting solely of 1-8 hydrogen substituted carbon atoms; and, preferably, 1-4 hydrogen substituted carbon atoms. The term xe2x80x9calkoxyxe2x80x9d refers to xe2x80x94Oxe2x80x94alkyl, where alkyl is as defined supra. Unless indicated otherwise, alkyl chains are optionally substituted within the alkyl chain or on a terminal carbon atom with 1 to 2 substituents.
The term xe2x80x9cheterocyclylxe2x80x9d refers to a saturated ring having five or six members of which at least one member is a N atom and which optionally contains one additional N atom. Examples include, and are not limited to, pyrrolidinyl, imidazolidinyl or pyrazolidinyl.
The term xe2x80x9carylxe2x80x9d refers to an aromatic monocyclic ring containing 6 hydrogen substituted carbon atoms such as phenyl.
The term xe2x80x9csuitable protecting groupxe2x80x9d as used herein refers to any of the known terminal moieties for protecting amino or hydroxy subsituents used in the art of organic synthesis as, for example, described in Principles of Peptide Synthesis, 2nd Ed., M. Bodanszky, Springer-Verlag, Berlin (1993); The Peptides, Vol 3, Protection of Functional Groups in Peptide Synthesis, eds E. Gross and J. Meienhofer, Academic Press, New York (1981); and, Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, (1991); which are hereby incorporated by reference.
When an amino acid side chain is optionally substituted with a suitable protecting group, the amino acid side chain will have amino or hydroxy substituents thus protected.
Examples of suitable protecting groups for substitution on a hydroxy substituent include, and are not limited to, methyl, benzyl, 2,4-(MeO2)benzyl, tetrahydropyranyl, tri(C1-6)alkylsilyl (such as trimethylsilyl (TMS) or triethylsilyl (TES)), t-butyl, 2-methoxyethoxymethyl (MEM), 4-(dimethylcarbamoyl)benzyl and phenoxyacetyl ethers. The hydroxy protecting group selected is preferably one that is easily removed in the reaction process.
Examples of suitable protecting groups for substitution on an amino substituent include, and are not limited to, acetyl (Ac), benzoyl (Bz), trifluoroacetyl (Tfa), toluenesulfonyl (Tos), benzyl (Bn), 2,4-(MeO2)benzyl, dibenzyl, triphenylmethyl (Trt), 2-(nitro)Ph-sulfenyl (Nps), benzyloxycarbonyl (Cbz or Z), t-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), 2-(bromo)benzyloxycarbonyl (2-Br-Z), 2-(chloro)benzyloxycarbonyl (2-Cl-Z), t-butyl-dimethylsilyloxycarbonyl, [2-(3,5-dimethoxyphenyl)-propyl-2-oxycarbonyl] (Ddz), 2,2,2-(trichloro)ethyloxycarbonyl (Troc), biphenylisopropyloxycarbonyl (Bpoc) and 2-(nitro)benzyloxycarbonyl.
The term xe2x80x9cindependentlyxe2x80x9d means that when more than one substituent is selected from a group, the substituents selected may be the same or different. xe2x80x9cDependentlyxe2x80x9d means that the substituents are specified in an indicated combination of structure variables.
The methods described above can be used to a plurality of intermediates from which a library of diverse pyrrolidine derivatives can be created.
This specification refers to substituents selected from a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain. The term xe2x80x9cnatural (L)xe2x80x9d refers to those amino acids having a xe2x80x9cLevoxe2x80x9d enantiomeric configuration and the term xe2x80x9cnon-natural (D)xe2x80x9d refers to those amino acids having a xe2x80x9cDextroxe2x80x9d enantiomeric configuration. In addition, certain abbreviations are used to refer to the amino acid side chains having the following meanings:
Throughout this specification, certain other abbreviations are employed having the following meanings, unless specifically indicated otherwise:
The generation of chemical libraries on and off resin has proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs from High Throughput screening. The current invention provides an invention process that allows for the assembly of highly complex drug-like molecules with defined stereochemistry. The key step of this invention is an Intramolecular Diels Alder reaction that allows most positions of the pyrrolidine to be easily modified.
In accordance with the invention, novel amino-acid derived triene precursors are prepared, on or off a solid support. These triene precursors undergo a Diels Alder cycloaddition reaction in situ, to yield the complex pyrrolidine intermediates which may be used to further prepare compound libraries.
Resin-bound or off-resin N-protected amino acid ester compounds used in the present methods are prepared according to methods known in the art (Sun, et al, J. Org. Chem., 1999, 64, 16, 5930-5940 and 5941-5945; Sun, et al, J. Org. Chem., 2000, 65, 2555-2559; Murray, et al, J. Org. Chem., 1999, 64 5930-5940) which are incorporated herein by reference.
Off-Resin Synthesis
An N-protected amino acid ester Compound A1 was acylated with a substituted acrylic acid Compound A2 using the appropriate solvents and conditions for a time period of from about 1 to about 10 hours at an appropriate temperature. The product was the amino-protected triene intermediate of Formula (Ic).
The triene Compound A3 was raised to an appropriate reflux temperature in an appropriate reflux solvent for a time period of from about 10 to about 168 hours to yield either the cyclized intermediate of Formula (I) or the ring opened pyrrolidine intermediate of Formula (II).
The cyclized intermediate of Formula (I) may also be prepared by a cycloaddition reaction forced by the addition of silica gel to the reaction mixture containing Compound A3. The ring opened intermediate of Formula (II) may also be prepared by further hydrolyzing the intermediate of Formula (I). 
Off-Resin Synthesis
For a compound selected from Formula (I), such as Compound B1 or Compound B2, the reflux temperature, solvent and time period is used to selectively determine the diastereomeric configuration of the 3a and 7a hydrogen atoms. 
Similarly, for a compound selected from Formula (II), the choice of reflux temperature, solvent and time period is used to selectively determine the diastereomeric configuration of the hydrogen atoms on the 3 and 4 position of the pyrrolidinyl ring and the diastereomeric configuration of X2, R3 and R4.
Resin-Bound Synthesis
To prepare Compound C3, a resin-bound N-protected amino acid ester Compound C1 (where R9 is not selected from R2 and R10 is not selected from R3) was acylated with a substituted acrylic acid Compound C2 using the appropriate solvents and conditions and shaken for an appropriate time at room temperature.
The triene Compound C3 was closed by a Diels Alder cycloaddition reaction to form the cyclized Compound C4, which was then removed from the resin as the intermediate of Formula (I). The ring opened pyrrolidine intermediate of Formula (II) is further prepared by hydrolysis of the cyclized intermediate of Formula (I). 
To prepare an isomeric intermediate of the present invention, the stereospecific nature of the starting materials used to prepare Compound C1 and reacted with Compound C3 selectively determine the diastereomeric configuration of the resulting intermediate selected from the group consisting of Formula (I) and Formula (II).
Nomenclature
Compounds are named according to nomenclature well known in the art and such nomenclature is exemplified using ring numbering as follows: 
Compound names can be generated using a nomenclature system based on these examples or may be generated using commercial chemical naming software such as the ACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario).